Jalbert L R, Rosen E D, Moons L, Chan J C, Carmeliet P, Collen D, Castellino F J
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, 3000 Leuven, Belgium.
J Clin Invest. 1998 Oct 15;102(8):1481-8. doi: 10.1172/JCI3011.
Matings of mice heterozygous for a protein C (PC) deficient allele, produced by targeted PC gene inactivation, yielded the expected Mendelian distribution of PC genotypes. Pups with a total deficiency of PC (PC-/-), obtained at embryonic day (E) 17.5 and at birth, appeared to develop normally macroscopically, but possessed obvious signs of bleeding and thrombosis and did not survive beyond 24 h after delivery. Microscopic examination of tissues and blood vessels of E17.5 PC-/- mice revealed their normal development, but scattered microvascular thrombosis in the brain combined with focal necrosis in the liver was observed. In addition, bleeding was noted in the brain near sites of fibrin deposition. The severity of these pathologies was exaggerated in PC-/- neonates. Plasma clottable fibrinogen was not detectable in coagulation assays in PC-/- neonatal mice, suggestive of fibrinogen depletion and secondary consumptive coagulopathy. Thus, while total PC deficiency did not affect the anatomic development of the embryo, severe perinatal consumptive coagulopathy occurred in the brain and liver of PC-/- mice, suggesting that a total PC deficiency is inconsistent with short-term survival.
通过靶向性蛋白C（PC）基因失活产生的携带PC缺陷等位基因的杂合子小鼠进行交配，产生了预期的PC基因型孟德尔分布。在胚胎期（E）17.5和出生时获得的完全缺乏PC（PC-/-）的幼崽，宏观上似乎发育正常，但具有明显的出血和血栓形成迹象，并且在分娩后24小时内无法存活。对E17.5 PC-/-小鼠的组织和血管进行显微镜检查发现它们发育正常，但观察到大脑中散在的微血管血栓形成并伴有肝脏局灶性坏死。此外，在纤维蛋白沉积部位附近的大脑中发现出血。这些病理变化的严重程度在PC-/-新生小鼠中更为明显。在PC-/-新生小鼠的凝血试验中未检测到可凝固的血浆纤维蛋白原，提示纤维蛋白原消耗和继发性消耗性凝血病。因此，虽然完全缺乏PC并不影响胚胎的解剖发育，但PC-/-小鼠的大脑和肝脏中发生了严重的围产期消耗性凝血病，这表明完全缺乏PC与短期存活不相容。
